Current treatments for asthma, while reducing exacerbations in a subset of patients by focusing on airway inflammation, do not eliminate them. There is no current innate immune modulator for the treatment of asthma. Asthma exacerbations are a significant cause of morbidity and mortality in asthma as they can lead to airway injury, lung function decline and death. The cause of an exacerbation is often an infection in the setting of abnormal airway inflammation. The response to infection is complex, involving both the innate and adaptive immune systems. Exacerbations in more severe asthmatics are of particular concern, as health care costs and lost productivity account for $21 billion/year in US annual health care expenditures. Thus, there is a critical need to develop new therapies to be used in the treatment of inflammatory lung diseases including asthma. The objective of this Phase I proposal is to develop new short peptide derivatives and mimetics of the active region of surfactant protein-A (SP-A), a protein that regulates key innate immune functions in the lung, and perform a drug screen that identifies those most active and stable with similar efficacy as the full-length protein. SP-A-derived peptides do not occur naturally and by synthetically produced analogs, we can create custom modifications with improved pharmacokinetic properties and stability. We will use asthma as our test model where SP-A peptide analogs modulate eosinophil and epithelial cell functions, key targets where cellular mechanisms drive the allergic asthma phenotype. The rationale for this study is based on our findings that the SP-A peptide reduces airway hyperresponsiveness (AHR), a fundamental characteristic of asthma, in two different pre-clinical mouse models of asthma. We have strong evidence to support that the mechanisms of protective action are due to 1) direct interaction with eosinophils to induce apoptosis and promote their resolution from the airway and 2) direct interaction with epithelial cells to inhibit mucin production. Therefore, our central hypothesis is that through direct effects upon airway eosinophil and epithelial cells, SP-A-derived peptides reduce airway inflammation and hyperresponsiveness associated with asthma. We propose to test this hypothesis through two specific aims. In Aim 1 we will synthesize, engineer and optimize peptides and structural mimetics derived from SP-A to identify a lead mimetic. In aim 2 we will characterize the bioactivity of SP-A-derived peptides and mimetics at specific cellular targets to identify a lead compound using a high throughput. Our company, RaeSedo LLC, was founded on the principle that we can create custom modifications with improved pharmacokinetic properties and stability for the development of this new class of asthma therapeutics.